ABSTRACT Untreated obstructive sleep apnea (OSA) is a precursor for several cardio-metabolic complications including hypertension, insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Despite advancements made in identifying an independent association between OSA and metabolic dysfunction, underlying mechanisms that explicate the association remain elusive. It is well established that intermittent hypoxemia and recurrent arousals, the two pathognomonic features of OSA, can activate the sympathetic nervous system, increase oxidative stress, and heighten systemic inflammation. Our preliminary data indicate that alterations in fat metabolism may also have a fundamental role in the causal chain between OSA and impairments in glucose homeostasis. Thus, the overarching objective of this proposal is to characterize aberrations in fat metabolism in OSA. To accomplish this objective, we will employ a combination of exceptionally unique methods for metabolic phenotyping and determine the putative roles of fat metabolism, skeletal and adipose tissue enzymatic activity, and toll-like receptor (TLR) signaling as mediators of metabolic dysfunction in OSA. Moreover, we will examine whether activity of several key skeletal muscle enzymes involved in ?-oxidation such as acyl-CoA synthase (ACS), carnitine palmitoyltransferase-1 (CPT-1), ?-hydroxyacyl-CoA dehydrogenase (?-HAD) and citrate synthase (CS) are altered in OSA. Finally, we propose to examine whether OSA interferes with extracellular triglyceride hydrolysis by decreasing the activity of lipoprotein lipase (LPL), which regulates FFA supply in various tissues for either storage or oxidation. The following two specific aims are proposed. Aim 1: To assess whether, independent of age, sex, race, and obesity, OSA severity is associated with alterations in: (1) whole body lipolysis and free fatty acid (FFA) oxidation; (2) subcutaneous adipose tissue lipolysis; (3) activity of skeletal muscle enzymes (ACS, CPT-1, ?-HAD, and CS) and TLR2/TLR4 expression; and (4) LPL activity in skeletal muscle and adipose tissue. Aim 2: To determine whether treatment of OSA with positive airway pressure (PAP) therapy will have salutary effects on: (1) whole body lipolysis and FFA oxidation; (2) subcutaneous adipose tissue lipolysis; (3) activity of skeletal muscle enzymes (ACS, CPT-1, ?-HAD, and CS) and TLR2/TLR4 expression; and (4) LPL activity in skeletal muscle and adipose tissue. Completion of these aims will add much needed mechanistic insight on how OSA alters glucose and fat metabolism and help open new therapeutic strategies (i.e., interruption of lipolysis) that could curtail the metabolic burden imposed by OSA particularly in those that are unable to use PAP therapy.